Exercise pressor reflex in peripheral artery disease: beneficial effects of heating and mechanisms

外周动脉疾病中的运动加压反射：加热的有益作用和机制

• 批准号: 9906271
• 负责人: JIAN CUI
• 金额: $ 74.74万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-05 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9906271
• 关键词: Afferent Neurons; Animals; Arteries; Atherosclerosis; Attenuated; Blood Pressure; Blood flow; Cardiovascular Diseases; Cardiovascular system; Control Animal; Data; Disease; Down-Regulation; Exercise; Exercise Tolerance; Exertion; Goals; Heating; Human; Hypertension; Intermittent Claudication; Intervention; Kidney; Knowledge; Leg; Lower Extremity; Muscle; Muscle Contraction; Nerve; Neurons; Oxygen; P2X-receptor; Pain in lower limb; Patients; Peripheral arterial disease; Play; Protocols documentation; Rattus; Reflex action; Role; Skeletal Muscle; Strenuous Exercise; Symptoms; Temperature; Testing; Thinness; Time; Translating; Walking; Work; afferent nerve; base; cardiovascular risk factor; clinically relevant; design; improved; interstitial; novel therapeutics; protein expression; receptor; response; treadmill; vasoconstriction

PROJECT SUMMARY ABSTRACT Peripheral artery disease (PAD) is atherosclerotic disease with a decrease in blood flow to the arteries of the lower extremities. Exaggerated sympathetic nerve activity (SNA) and blood pressure (BP) are observed during intense exercise activity in this disease and these responses worsen exercise tolerance. The major goal of this proposal is to examine if heat exposure and heat treatment have beneficial effects on PAD. We will explore this clinically relevant hypothesis via examining the following specific aims utilizing both animal and human studies. 1. To examine the effects of heat exposure (i.e. whole body heating or local heating) on the exercise pressor reflex (EPR). We hypothesize that heat exposure attenuates amplified EPR in PAD. In human studies, muscle sympathetic nerve activity (MSNA) and BP responses to exercise will be examined during whole body heating or local muscle heating in PAD patients and healthy control subjects. We speculate that MSNA and BP responses will be accentuated in PAD patients as compared with healthy controls and these augmented responses will be significantly attenuated by heat exposure. In animal studies, renal SNA and BP responses to static muscle contraction will be examined in PAD rats and in control rats. We speculate that EPR will be enhanced in PAD rats and increasing muscle temperature by heat exposure will attenuate the amplified reflex. 2. To examine the engagement of temperature-sensitive P2X receptors in the effects of heat exposure on the EPR. We hypothesize that heat exposure decreases the levels of ATP in the muscle insterstitium and thereby attenuates amplification of the EPR in PAD. In animal studies, we speculate that heat exposure will attenuate the levels of interstitial ATP to a greater degree in PAD rats than in control rats. We further speculate that P2X subtype (i.e., P2X3) will play a role in regulating the EPR in PAD after heat exposure. 3. To examine the effects of heat treatment (i.e. a prior heat exposure) on BP response during walking in PAD patients and further to examine potential P2X mechanisms using animal studies. After a heat treatment, walking ability in PAD patients will be estimated on a treadmill with a Gardner protocol. We speculate that the BP response will be lower and the skeletal muscle oxygenation (SmO2) level will be higher than those without the heat treatment at the same stage of the walk protocol. Moreover, the heat treatment may increase peak treadmill walking time. In animal studies, we hypothesize that heat treatment attenuates expression, function and response of P2X3 in PAD. We will examine the protein expression levels of P2X3 in muscle afferent nerves of PAD rats. We speculate that heat treatment will decrease P2X3 in PAD rats. We further speculate that heat treatment will attenuate the amplification of P2X3 current amplitude in sensory neurons innervating muscle afferents in PAD rats and this thereby inhibits the exaggerated EPR.

项目摘要 外周动脉疾病（PAD）是动脉粥样硬化性疾病，其特征是动脉血流减少， 下肢交感神经活动（SNA）和血压（BP）在 这种疾病的剧烈运动活动和这些反应恶化运动耐量。这个项目的主要目标是 建议是检查热暴露和热处理是否对PAD有有益影响。我们将探讨这一点 通过使用动物和人体研究检查以下特定目的，确定临床相关假设。 1.检查热暴露（即全身加热或局部加热）对运动的影响 升压反射（EPR）。我们推测热暴露减弱了PAD中放大的EPR。在人类研究中， 肌肉交感神经活动（MSNA）和BP对运动的反应将在全身检查 PAD患者和健康对照受试者的局部肌肉发热或局部肌肉发热。我们推测MSNA和BP 与健康对照组相比，PAD患者的反应将加重， 热暴露会显著减弱反应。在动物研究中，肾SNA和BP对 在PAD大鼠和对照大鼠中检查静态肌肉收缩。我们推测EPR将是 在PAD大鼠中增强，并且通过热暴露增加肌肉温度将减弱放大的反射。 2.研究温度敏感性P2X受体在热暴露效应中的作用 关于EPR我们假设热暴露降低了肌肉间质中ATP的水平， 从而减弱PAD中EPR的放大。在动物研究中，我们推测热暴露会 降低PAD大鼠间质ATP水平的程度大于对照大鼠。我们进一步推测 该P2X亚型（即，P2X3）对PAD热暴露后的EPR起调节作用。 3.检查热处理（即既往热暴露）对步行过程中BP反应的影响 PAD患者，并使用动物研究进一步检查潜在的P2X机制。经过一场热 在治疗期间，将使用Gardner方案在跑步机上评估PAD患者的行走能力。我们推测 BP反应将较低，骨骼肌氧合（SmO2）水平将高于 而不需要在Walk方案的相同阶段进行热处理。此外，热处理可增加 跑步机行走高峰时间。在动物研究中，我们假设热处理减弱了表达， P2X3在PAD中的功能和反应。我们将检测P2X3蛋白在肌肉传入纤维中的表达水平， PAD大鼠的神经。我们推测热处理将降低PAD大鼠的P2X3。我们进一步推测， 热处理会减弱支配肌肉的感觉神经元P2X3电流幅度的放大 在PAD大鼠的传入，从而抑制夸大的EPR。